Our Section collaborates with several molecular geneticists laboratories on behavioral phenotyping of transgenic and knockout mice with mutations in genes expressed in the brain, relevant to our research interests in animal models of neuropsychiatric diseases. Over the past years, we have developed and refined a multitiered strategy for mouse behavioral phenotyping. Rigorous methods for quantitate observations of general health, home cage behaviors, tests for sensory abilities, and motor functions, are designed to ensure that the mutant line has no gross physical defects that would produce false positives on more complex behavioral tasks. This strategy reduces false negatives in the first characterization of a new mutant line. Further, we have developed new behavioral tasks for mice, and adapted rat behavioral tasks for mice. A constellation of ccomplementary tests is conducted to test hypotheses about gene function within each relevant behavioral domain, e.g. memory, feeding, motor coordination, anxiety, and social behavior. During the past year, these methods were further refined and validated for three novel cognitive tasks, in a comparison across inbred strains of mice that are widely used in behavioral genetics. Trace fear conditioning was high in C57BL/6J and 129S6/SvEvTac but impaired in DBA/2J. Barnes maze spatial learning was good in C57BL/6J and DBA/2J but poor in 129S6/SvEvTac. The social transmission of food preference olfactory memory task was acquired similarly by all three strains. These data support the use of C57BL/6J as the optimal breeding strain for analyses of more challenging cognitive tasks, particularly for targeted gene mutations predicted to reduce performance. During the past year, our approach has been applied to the characterization of the serotonin transporter (5-HTT) knockout mouse, generated by Dr. Dennis Murphy and coworkers here in the NIMH IRP. Postdoctoral fellow Andrew Holmes found a striking anxiety-like phenotype that was confirmed in three different anxiety tasks, the elevated plus maze, the light/dark transitions task, and the emergence test in an open field. Aggression scores were lower in 5-HTT -/- as compared to +/+ wildtype littermate controls. Depression-related tasks revealed normal baseline behaviors in 5-HTT -/- but lack of response to antidepressants that act through the serotonin transporter. A striking obesity phenotype was apparent at older ages in the 5-HTT -/-. Dr. Holmes and members of Dr. Murphy's laboratory found normal levels of daily food consumption, but somewhat lower levels of home cage activity and metabolic differences, that may be responsible for the high body weights in 5-HTT -/- mice. Since serotonin is involved in several human neuropsychiatric disorders, and 5-HTT antagonists such as Prozac are commonly used to treat depression, the 5-HTT mutant mouse represents a useful model system to further understand the role of serotonergic neurotransmission in mental illnesses. Additional publications listed for this project year describe collaborative experiments completed in earlier years and published this year.